Although molecular analysis has failed to reveal consistently occurring genetic alterations in human prostate cancer, both dominantly acting oncogenic activities as well as loss of growth suppressor functions have been identified. Oncogenic mutations in the c-Ha-ras gene as well as abnormally elevated c-myc mRNA levels have been detected in human prostate cancer. In addition, early studies demonstrating allelic loss and, more recently, mutations in the retinoblastoma and p53 gene indicate that loss of growth suppressor functions are involved in progression. As in other cancers, potentially synergistic relationships between these two general classes of genetic alterations during carcinogenesis have not been established. Experimental approaches which focus on the normal function of proto- oncogenes and growth suppressor genes have thus far failed to provide an understanding of synergistic relationships between these two classes. One approach to this dilemma is to establish an in vivo model system where these activities can be independently manipulated and the resulting phenotypic alterations investigated at the molecular and cellular level. This approach will establish complementation relationships that can be applied to the development of objective molecular markers for prostate cancer in man. We will use a transgenic/mouse prostate reconstitution (TMPR) model system to study the complementation relationships between dominantly acting oncogenes and loss of normal p53 function. Recent studies suggest that loss of normal p53 function is highly selected for during ras+myc-induced carcinogenesis using the reconstitution model. As we have previously documented that ras, myc and ras+myc activities produce unique phenotypic alterations using normal wild type prostate tissues, the impact of a p53- null environment on these phenotypic alterations can be clearly elucidated. Initially the ras and myc oncogenes will be introduced singly or together into total urogenital sinus tissue derived from p53-null mice. This approach will be extended via similar studies which involve gene transfer that is restricted to the mesenchymal or epithelial compartment. We will subsequently use transgenic mouse urogenital sinus tissues containing specific p53 mutations for similar studies. Cell lines derived during these studies will provide useful substrates for evaluating mechanisms involved in loss of p53 function which may be unique to prostate cancer and for testing the biological activities of growth modulators. These studies will result in the classification of complementation relationships between the presence of relevant dominantly acting oncogene activities and loss of growth suppressor function and thus illuminate the clinical significance of these molecular markers in prostate cancer.